was shown to be physically associated with the spliceosome, and its enzymatic activity was necessary for the early steps of spliceosome assembly. Ser/Thr phosphatases are important regulators of both constitutive and AS events, as it was suggested by pioneering studies showing alternative 5 splice selection after addition of PP1 in splicing assay in vitro. Furthermore, PP2C was shown to interact with the RBP YB-1 and to modulate AS of the CD44 gene, while PP1 was demonstrated to interact with a short motif RVXF motif within the RRM of several splicing factors, like SRSF1, SRSF9, and the SR-like protein TRA2-. Dephosphorylation of TRA2- by PP1 positively modulates its dimerization and its interaction with partner proteins, like SRSF1. Moreover, PP1 regulates alternative splice selection in TRA2- target mRNAs like the SMN2 gene. Exclusion of the exon 7 of SMN2 gene, combined with the primary deletion of SMN1 gene, is the cause of the spinal muscular atrophy . TRA2- promotes the inclusion of the exon 7 of SMN2 favoring the production of a functional full length protein. TRA2- splicing activity is enhanced by inhibition of PP1 activity and, surprisingly, by 
activation of PP2A. Indeed, the Stamm’s group found that a class of compounds derivative from cantharidin activates PP2A, which in turn dephosphorylates TRA2- on Thr33, favoring inclusion of exon 7. These observations suggest the possibility to develop new protein phosphatase inhibitors that could be used for the therapeutic correction of the splicing defects occurring in neurodegenerative diseases like SMA. Modulating protein phosphatases’ activity in order to manipulate pathogenetic splicing events has been suggested as a potential therapeutic tool also for cancer treatment. Indeed, it has been shown that genotoxic agents inducing apoptosis in cancer cells act through the generation of PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19818716 ceramide and activation of PP1, which in turn promotes the formation of the proapoptotic – and CASPASE-9b splice variants. On the other hand, it has been shown that the proapoptotic activity of synthetic ceramides, like C6 pyridinium ceramide, is instead associated with activation of PP1 and the consequent reduced phosphorylation of several splicing factors and modulation of several splicing events. These observations underline the importance of the regulated activity of protein phosphatases for proper regulation of the splicing process and strongly suggest the possibility to develop new molecules targeting their activity, International Journal of Cell Biology which could be used for the therapeutic correction of the splicing defects occurring in several human diseases. 10. Concluding Remarks Increasing evidence points out to a key role of misregulation of AS in the cellular transformation process. Cancerspecific splice variants can potentially be used as accurate diagnostic and prognostic markers, as it was recently highlighted by genome-wide studies. Targeting the splicing process represents, therefore, an attractive therapeutic target for cancer treatment, and it is currently under intense investigation. Therapeutic modulation of AS is mainly realized through RNA-based technologies or through chemical reagents inhibiting spliceosome activity. The RNA-based technologies exploit antisense oligonucleotide masking specific sequence elements to splicing factors and/or the spliceosome, whereas chemical approaches make use of drugs that GSK126 directly target the activity of spliceosomal components, as for examples